Colorectal cancer (CRC) is the third most common and third most deadly cancer in the US. Current evidence suggests that CRC incidence is increasing among both men and women younger than 50 years of age, who are also more likely to be diagnosed with late-stage disease. Additionally, there is a significant racial disparity, in that African American men and women experience a higher incidence of colorectal cancer compared to white men and women, and an even higher rate of death from colorectal cancer compared to the white population. Recent studies suggest that infection with Helicobacter pylori, a known gastric-cancer carcinogen, may also increase the risk of CRC, although these findings have been inconsistent. Two recent meta-analyses found statistically significant 40% to 50% increased odds for CRC among H. pylori-positive individuals. However, the majority of the studies surveyed did not take into account the H. pylori sub-type. It is known that, as H. pylori has evolved over 50,000 years to live in the human stomach, the bacteria have become highly diverse genetically. The proposed project builds on our work in the Southern Community Cohort Study, in which we found a statistically significant 60-80% increase in the odds of CRC for individuals sero-positive for one of five specific H. pylori proteins. For colon cancer alone, thes associations were stronger, so that sero- positivity to any of these five proteins was associated with a significant, approximate two-fold increased risk, most prominently for the known H. pylori virulence factor VacA (OR for VacA sero-positivity, 2.24). The association of VacA sero-positivity was particularly strong for CRC that has distant spread (OR, 5.67), among younger (<55 y) individuals (OR, 3.48), and for cancer of the right colon (OR, 3.13). Furthermore, a strong, significant, positive dose-response association across increasing quartiles of VacA antibody level was also observed. The current project seeks to produce the most definitive study to date of the H. pylori-CRC association through evaluation of the association in a large, collaborative nested case-control study (including over 4,000 prospectively-ascertained cases from 10 cohort studies spanning the US, and 1:1 matched controls), assessment of differences in the association by time from blood collection to diagnosis, and examination of the potential interaction of regular aspirin use on the association of H. pylori protein-specific infection with CRC risk. Thus, the current project allows us to thoroughly evaluate the novel association between Helicobacter pylori protein-specific infection and CRC risk, particularly for aggressive disease, building the groundwork for significantly strengthening CRC prevention and screening strategies with a new risk biomarker. Furthermore, this project provides the opportunity to potentially identify an infectious exposure to a common cancer that may be modifiable by a regimen of regular aspirin use, and moreover has already been proven to be modifiable through the use of H. pylori-eradication therapy and, thus, possibly holds great promise as a CRC prevention strategy.